Primary attention is focused on experiments to define the immune pathogenesis of spontaneous diabetes in the BB rat, an animal model with many features in common with the human disease. Since we have found that transplanted islets succumb to the same autoimmune damage which destroys the native islets, islet grafts will be employed as a probe to investigate the phenomenon of MHC restriction in autoimmune islet damage. Employing inbred and congenic strains of rats attempts will be made to locate the region of MHC responsible for restriction phenomena. The fate of antigen presenting cell depleted islet grafts will be studied in immunologically tolerant hosts to identify and characterize the activity of effector cells involved in islet damage. Investigations are also planned to determine whether the islet damage seen in these tolerant hosts is caused by an aberrant differentiation of normal stem cells in an autoimmune milieu which results in autoreactive cells in these hosts. Examination of the role of thymic education of T cells and MHC restriction patterns of diabetogenic effector cells is a major goal of the grant. Aspects of the proposed studies which are of possible immediate practical importance are: 1) perfection of islet transplant techniques; 2) markers for prediabetic states; 3) development of safe and effective immunosuppression as treatment or prophylaxis of diabetes.